As early as 1750 it was recognized that green vegetables
and citrus fruits could prevent the dread disease scurvy,
which afflicted ancient sea voyagers, causing hemorrhages
of skin, gums, and joints, followed by death. At about that
time, Captain James Cook showed that sailors could avoid
scurvy during long voyages by eating local green vegetables
and grasses. Soon thereafter British seamen became
“limeys.” The chemical structure of the active component,
vitamin C (Fig. 1), was established in 1933. In a similar
way, from about 1830 cod liver oil was used to prevent
rickets. The active ingredient was vitamin D (Fig. 1).
Later, vitamin A (Fig. 1), also present in cod liver oil,
was recognized for its prevention of night blindness and
maintenance of healthy skin. In oriental countries the disease
beriberi, with its strange paralysis called polyneuritis,
killed millions. A persuasive demonstration that this was a
deficiency disease came in 1893 when Eijkman, working
in Indonesia, demonstrated that chicks fed the white rice
consumed by the local populace developed a rapidly fatal
paralysis. However, the chicks could be completely cured
by prompt feeding of a rice bran extract. It was 1926 before
the curative compound was isolated from rice bran,
characterized chemically, and named thiamin (Fig. 2). In
1912 the Polish biochemist Casimir Funk proposed that
the four diseases scurvy, beriberi, pellagra, and rickets resulted
from the dietary deficiency of vital nutrients which
he imagined to be amines. He called them vitamines.

Figure 1 The structures of vitamins A, C, and D.

Figure 2 The vitamin thiamin
and its coenzyme form thiamin
diphosphate (thiamin
pyrophosphate).

At about the same time, McCollum and Davis and others
discovered that rats fed on semi-artificial diets required
small amounts of “accessory growth factors.” Growth of
rats required both a fat-soluble material A and a watersoluble
material B. Factor A, which could be found in
milk, was later shown to consist of what we now call vitamins
A, D, and E (Fig. 3). In 1939 another essential
fat-soluble nutrient, vitamin K (Fig. 3), was isolated from
plant sources. It was designated K for koagulation, because
it was needed for blood clotting. The water-soluble
factor B cured beriberi in chicks. However, it was also
shown to consist of several components, and could better
be described as a B complex. The beriberi curative factor
thiamin, which was easily destroyed by heat, was designated
B1. Another nutritionally essential component, B2,
was stable to heat. The major growth-stimulating component
of B2, the yellow fluorescent compound riboflavin
(Fig.4), was designated vitamin B2. Other water-soluble
components were identified using a variety of tests. Nicotinamide
was found in the coenzyme nicotinamide adenine
dinucleotide (NAD; see Fig.8) in 1935. Thecorresponding
carboxylic acid nicotinic acid (also called niacin, Fig. 4)
is also an active vitamin. It was a well-known compound
that had been prepared in 1867 by oxidation of nicotine,
but had not been recognized as a nutrient until 1935 when
it was shown to cure “black tongue” of dogs and shortly
thereafter human pellagra. Biotin (Fig. 4) was first identified
as a growth factor for yeast. Pantothenic acid (Fig. 4),
which is present in plentiful amounts in many foods, was
recognized as a curative agent for a dermatitis of chicks.
Vitamin B6 (Fig. 5) prevented a facial dermatitis in rats
(“rat pellagra”). Folic acid, first described by Lucy Wills in
Bombay, was identified as a vitamin that cured a macrocytic
anemia that was often associated with pregnancy.

Figure 3 Structures of vitamins K and E and of the related ubiquinone (coenzyme Q) and plastoquinone.

The curative material, which is abundant in green leafy
vegetables, was named folic acid. However, this name is
usually reserved for the synthetic compound used in dietary
supplementation. The natural forms are largely the
coenzymes (Fig. 6), which are collectively called folates.
The last of the accepted human vitamins to be discovered
was vitamin B12. A cobalt-containing organic compound
needed in very small amounts, it cures and prevents pernicious
anemia, which was often a fatal disease of people
over 60 years of age. Its complex structure (Fig. 7)
was determined by X-ray diffraction after numerous efforts
at chemical characterization had failed. However,
cyanocobalamin, thecompoundisolatedandtheformused
in nutritional supplementation, is an artifact of the isolation
and synthesis. The natural vitamin may have OH in
place of CN but consists largely of the coenzyme forms.

Figure 4 Four components of the vitamin B complex: riboflavin, nicotinamide, biotin, pantothenic acid, and the acyl
carrier carnitine. Thiamin (vitamin B1, Fig. 2) is also a member of the B complex. Carnitine, which has an essential
acyl carrier function in the human body, is a vitamin for flour beetles.

Have all of the vitamins been discovered? Rodents
have been reared on almost completely synthetic diets.
However, good health in human beings may require additional
materials. For example, some essential compounds
might be
made by intestinal bacteria. Some essential coenzymes
such as lipoic acid, ubiquinone (coenzyme Q),
and pyrroloquinoline quinone (PQQ) may be vitamin-like.
Their presence in foods may be beneficial. Some individuals
may need as dietary components these compounds,
which are normally made by the body. Another example
is the acyl-carrier molecule carnitine (Fig. 4), which
is a growth factor needed by a common species of flour
beetle, but is synthesized in adequate amounts by most human
individuals. However, a few children require dietary
carnitine. Inositol is an essential growth factor for yeast
and is sometimes regarded as a vitamin. Flavonoid compounds,
abundant in citrus fruit and other plant sources,
have also sometimes been classified as a vitamin. Several
amino acids, common constituents of proteins, must also
be present in the human diet. These are needed in relatively
large amounts and are not classified as vitamins. The role
of small amounts of another amino acid taurine, which is
essential for cats, in human nutrition is of current interest.
The essential omega-3 and omega-6 fatty acids are also
necessary dietary constituents, as are numerous metallic
elements.

Figure 6 The coenzyme tetrahydrofolic acid (tetrahydropteroylglutamic acid). The vitamin folic acid has two additional
double bonds (dashed) in the second ring. Most of this coenzyme exists within cells as more complex forms
containing additional glutamic acid units attached to the side chain at the upper right.

The discovery of coenzymes and catalytic prosthetic
groups came in part from biochemical studies of yeast,
of alcoholic fermentation, and of respiration. Buchner
in 1899, discovered that a cell-free juice prepared from
freshly ground active yeast cells still fermented sugar.
Pasteur and others had previously maintained that fermentation
required intact cells. Dialysis of the yeast
juice stopped the fermentation, but the material that diffused
out, which was called cozymase, could be added
back with restoration of the fermentation ability of the
juice. Cozymase was soon found to consist of a
mixture
of the nicotinamide-containing compound now called
NAD (Fig. 8), magnesium ions, and thiamin diphosphate
(Fig. 2). NAD was quickly recognized as a component of a
“respiratory chain” in animal and yeast cells. Since about
1910 this chain has been recognized as beginning with the
hemoglobin-like oxygen-binding protein cytochrome oxidase
and an intensely yellow flavin compound that was
identified as the riboflavin derivative FAD (Fig. 9). The
cooperative functioning of these vitamin-containing compounds,
together with associated proteins, established the
concept of coenzymes. Additional compounds, isolated
from natural materials, containing vitamin B6, pantothenic
is a growth factor needed by a common species of flour
beetle, but is synthesized in adequate amounts by most human
individuals. However, a few children require dietary
carnitine. Inositol is an essential growth factor for yeast
and is sometimes regarded as a vitamin. Flavonoid compounds,
abundant in citrus fruit and other plant sources,
have also sometimes been classified as a vitamin. Several
amino acids, common constituents of proteins, must also
be present in the human diet. These are needed in relatively
large amounts and are not classified as vitamins. The role
of small amounts of another amino acid taurine, which is
essential for cats, in human nutrition is of current interest.
The essential omega-3 and omega-6 fatty acids are also
necessary dietary constituents, as are numerous metallic
elements.

The discovery of coenzymes and catalytic prosthetic
groups came in part from biochemical studies of yeast,
of alcoholic fermentation, and of respiration. Buchner
in 1899, discovered that a cell-free juice prepared from
freshly ground active yeast cells still fermented sugar.
Pasteur and others had previously maintained that fermentation
required intact cells. Dialysis of the yeast
juice stopped the fermentation, but the material that diffused
out, which was called cozymase, could be added
back with restoration of the fermentation ability of the
juice. Cozymase was soon found to consist of a mixture
of the nicotinamide-containing compound now called
NAD (Fig. 8), magnesium ions, and thiamin diphosphate
(Fig. 2). NAD was quickly recognized as a component of a
“respiratory chain” in animal and yeast cells. Since about
1910 this chain has been recognized as beginning with the
hemoglobin-like oxygen-binding protein cytochrome oxidase
and an intensely yellow flavin compound that was
identified as the riboflavin derivative FAD (Fig. 9). The
cooperative functioning of these vitamin-containing compounds,
together with associated proteins, established the
concept of coenzymes. Additional compounds, isolated
from natural materials, containing vitaminB6, pantothenic
acid (coenzyme A, Fig. 10), folic acid, and vitamin B12 are among many substances that are now described as
coenzymes.

NAD, NADP, and thiamin diphosphate were found to
bind reversibly to their host proteins. NAD and NADP, as
their reduced (NADH, NADPH) and oxidized (NAD+,
NADP+) forms (Fig. 8), were found to act as hydrogen
carriers, moving freely between two or more catalytic
proteins. In contrast, FAD and pyridoxal phosphate
(PLP, Fig. 5) are extremely tightly bound to some proteins
and normally function without dissociation from the
catalytic protein. Still others, such as biotin, are covalently
bonded to proteins (Fig. 11). The same is true of
some FAD derivatives. These tightly bound cocatalysts
are often referred to as prosthetic groups. These include
a great variety of both organic and metallo-organic structures.
Among the latter are the heme proteins. Vitamin
C (ascorbic acid or ascorbate; Fig. 1) is unusual in functioning
largely in a free, unbound form, and often at a
very high concentration. This is also consistent with its
high nutritional requirement for human beings. Vitamin A
has a special role in vision. The aldehyde retinal (Fig. 1)
combines with proteins of the retina to form the light receptors
of the visual cells. Vitamin K has a specialized
function in formation of a series of proteins needed for
blood clotting. Both vitamin A (as retinoic acid) and vitamin
D (as hydroxylated derivatives) serve as important
hormones.